In the previous funding period, we focused on identifying the role of the bone marrow (BM) microenvironment in conferring growth, survival, and drug resistance in multiple myeloma (MM) cells. Importantly, we have successfully translated multiple novel agents (bortezomib, lenalidomide) targeting these interactions from the bench to the bedside and FDA approval for treatment of MM. Our prior studies have focused on the cellular components of BM milieu including fibroblasts, osteoclasts, osteoblasts, and endothelial cells. In this renewal application, we will focus on characterizing the role of plasmacytoid dendritic cells (pDCs), predominantly localized in the MM BM, in the pathophysiology of MM. Our data show that pDCs are dysfunctional in MM, since they do not stimulate T cell responses. Importantly, they induce MM cell growth and survival even in the presence of conventional and novel drugs. The current proposal therefore attempts to enhance our understanding of the intercellular interaction of MM cells with pDCs and its therapeutic relevance, and specifically addresses three inter-related hypotheses: 1) the biological behavior of MM cells is modulated by their interactions with pDCs; 2) the molecular and functional sequelae of pDC-MM interactions represent potential therapeutic targets; and 3) the aggregate interplay of these interactions in vivo allows for the rational design of novel single and combination targeted therapies. Based on these hypotheses, the current proposal focuses on a set of distinct, yet mutually interacting and complementary. Specific Aims. We propose: to characterize the role of pDCs in MM cell growth, survival, drug resistance and migration in vitro (Specific Aim 1); to identify the molecular and cellular mechanisms mediating pDC-MM interactions and validate their functional significance and therapeutic relevance (Specific Aim 2); and to validate novel therapies targeting molecular and cellular mechanisms mediating pDC-MM interactions in vivo using MM animal models for evaluation in phase-I/II clinical trials (Specific Aim 3). Overall, these studies will provide the basis for either directly targeting pDCs or blocking the pDC-MM interaction in novel therapeutic strategies for MM to enhance MM cytotoxicity, overcome drug-resistance, and improve patient outcome.